The present invention is concerned with an improved antiinflammatory composition and method of treating inflammation which employs a nonsteroidal antiinflammatory agent (e.g. indomethacin or an oxicam such as piroxicam, sudoxicam, tenoxicam, isoxicam; the generic names used here and elsewhere herein are from the USAN and the USP Dictionary of Drug Names, 1961-1981, Griffiths et al., ed., U.S. Pharmacopeial Convention Inc., Rockville, Md., 1984) in combination with a histamine-H.sub.2 -antagonist selected from the group consisting of 2-guanidino-4-(4-imidazolyl)thiazole, 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole, 2-(N-benzyl-N'-guanidino)-4-(2-methyl-4-imidazolyl)thiazole, 2-(N-pentyl-N'-guanidino)-4-(2-methyl-4-imidazolyl)thiazole and 2-guanidino-4-[2-(hexylamino)-4-imidazolyl]thiazole.
Gastrointestinal irritation, sometimes culminating in ulcers, is a side effect commonly associated, to one degree or another, with nonsteroidal antiinflammatory agents. (For an essentially complete summary of known nonsteroidal antiinflammatory agents, see Goldenberg, U.S. Pat. No. 4,447,443.) In many cases, individuals requiring such antiinflammatory treatment are precluded from enjoying the benefits thereof because of their susceptibility to such irritation or ulcers. The present combination of antiinflammatory agents with H.sub.2 -antagonist agents (which are gastric acid antisecretory agents, or gastric acid antisecretory agents and show cytoprotective activity as well) permits desirable antiinflammatory therapy while preventing or ameliorating said gastrointestinal irritation and ulcers. In addition, in certain cases, there is an enhancement of the beneficial effect in the treatment of rheumatoid arthritis with the present combination.
Other histamine-H.sub.2 -antagonist (gastric secretory inhibitory) compounds such as ranitidine, cimetidine and 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propylamino]]-1H-1,2,4-tria zole-3-methanol, have been previously combined with indomethacin, piroxicam and other antiinflammatory agents for this purpose. See for example U.K. Patent Applications Nos. 2,105,193 and 2,105,588; and Lovelace, U.S. Pat. No. 4,230,717. More recently, the histidine decarboxylase inhibitor, alphafluoromethylhistidine of Kollonitsch et al., U.S. Pat. No. 4,325,961, has been reported to provide synergistic antiinflammatory activity, particularly with indomethacin, Goldenberg, U.S. Pat. No. 4,447,443. The ulcerogenicity of this combination is not discussed.
The use of 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole per se in the treatment of rheumatoid arthritis is the subject of U.S. patent application, Ser. No. 659,750 by Larson, filed on Oct. 11, 1984, concurrently with the parent of the present application. Improved antiinflammatory salts of piroxicam, including a salt with 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole, are the subject of U.S. patent application Ser. No. 659,733 by Lombardino, also filed on Oct. 11, 1984.
The antiinflammatory agents employed in the present invention are known. For example The Merck Index, 10th Ed., 1983 contains, among others, monographs concerning indomethacin (No. 4852), isoxicam (No. 5085), piroxicam (No. 7378) and tenoxicam (No. 8980). Preparation of the oxicams and their utility as antiinflammatory agents are further disclosed in U.S. Pat. Nos. 3,591,584; 3,787,324; 3,822,258; 3,892,740; and 4,434,164.
The histamine-H.sub.2 -antagonists of the present invention are also known (see U.S. Pat. Nos. 4,435,396 and 4,374,843), or, in the cases of 2-(N-benzyl-N'-guanidino)-4-(2-methyl-4-imidazolyl)thiazole and 2-(N-pentyl-N'-guanidino)-4-(2-methyl-4-imidazolyl)thiazole, are the subject of copending U.S. application Ser. No. 605,510, of Reiter filed Apr. 30, 1984, for "2-(N-Substituted guanidino)-4-heteroarylthiazole Antiulcer Agents." The method of preparing said N-benzyl and N-pentyl guanidino compounds and employing same as an antiulcer and/or as a gastric antisecretory agent is also detailed hereinafter. Also detailed hereinafter, but not here claimed, is an improved method of preparing 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole and certain of its salts.